Blend compositions for oral administration as a rapidly dissolving powder and/or suspension

ABSTRACT

Disclosed is a dry powder oral formulation that includes an active pharmaceutical ingredient (API), a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a pharmaceutically acceptable preparation. Also disclosed are an excipient composition in absence of an API and methods of making and using the formulations and compositions. Also disclosed is a chewable, swallowable, and/or orally disintegrating tablet comprising an active pharmaceutical ingredient (API), a lecithin powder, a galactomannan, one or more sweetening agents, one or more flavoring agents and an organic acid in a pharmaceutically acceptable preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/591,427, filed Oct. 2, 2019, which is a continuation of U.S.application Ser. No. 15/838,254 filed Dec. 11, 2017, now issued as U.S.Pat. No. 10,471,006, on Nov. 12, 2019, which claims priority from U.S.Provisional Application Ser. No. 62/529,170 filed on Jul. 6, 2017, whichis incorporated herein by reference in its entirety.

FIELD

The present invention relates to pharmaceutically acceptableformulations of orally administered substances, and more particularly toformulations for orally administering substances, the individualformulations being administrable in either a dry powder form or with asmall quantity of water (as preferred by the subject), and to methodsfor preparation and administering the substances.

INTRODUCTION

Patient acceptance of medications, often referred to as patientadherence, has been reported to average 50% in developing countriesaround the world (1). Although a number of factors may contribute to the50% lack of adherence, characteristics of the drug formulation may be ofparticular importance. For example, oral tablet formulations cansometimes cause dysphasia and/or nausea and vomiting in patients (2).Further, unpleasant taste may be a challenge in administering a medicineparticularly for children (3, 4).

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug(NSAID) with multiple beneficial effects including pain relief andreduction of inflammation and fever. (5, 6). Nevertheless, patientadherence may be a challenge in treatment with ibuprofen as well asother NSAIDs (7, 8).

Additionally, formulations which are administrable both in dry powderform and in suspension by adding a minimum quantity of water to dissolvethe dry powder are not available on the market. Powder, solution, andsuspension dosage forms typically utilize a different set of excipientsto achieve acceptable physical properties. For a powder, excipients arechosen on the basis of achieving acceptable physical properties such asflow, density, and compactability. For a solution and suspension dosageforms, excipients are chosen on the basis of achieving acceptableproperties such as solubility, suspendability, dispersability, andviscosity. For flavored powders, solutions, and suspensions, the typeand concentration of sweeteners and flavors are typically differentsince the sensory perception of flavor and texture would be differentwhen consuming a powder versus a liquid dosage form. Also, taste maskingof active pharmaceutical ingredients (API) are typically dependent ontype, concentration, and processing method (i.e., API coating, granulecoating, etc.) of excipients.

Therefore, what is needed is a formulation which is administrable bothin dry powder form and in suspension by adding a minimum quantity ofwater to dissolve the dry powder.

SUMMARY

Accordingly, the inventors herein have succeeded in devisingformulations that can be administered either as a dry powder or in asmall quantity of water. The new formulations provide improved taste andmouthfeel to facilitate ease of administration and patient adherence.

Thus, in various embodiments, the present invention is directed todry-powder oral formulations that include an active pharmaceuticalingredient (API), a lecithin powder, a galactomannan, one or moresweetening agents, one or more flavoring agents and an organic acid in apharmaceutically acceptable preparation. In various embodiments, thedry-powder formulation includes ibuprofen; sunflower lecithin powder;guar gum; xylitol and isomalt; cherry, strawberry and raspberryflavorings, grape flavoring, orange flavoring, other fruit flavors, andcitric acid, malic acid, fumaric acid, or any other acidulants, andcombinations of any of the following, in a pharmaceutically acceptablepreparation. In various aspects, the formulation solubility ordispersability in water is no more than about 0.5 w/v. In variousaspects, the formulation or an aqueous solution or dispersion thereof isin a unit dosage form in a container selected from the group consistingof a blister foil pack, stick pack, sachet, pouch, bottle, orallydisintegrating tablet, dispersible tablet, capsule, powder in a capsule,and spheres in a capsule. In various aspects, the unit dosage form ofibuprofen is in a quantity of about 50, about 100, about 200, about 400,about 600 or about 800 mg.

In various other embodiments, the present invention is directed to amethod of administering an API. The method includes providing adry-powder oral formulation of the API, a lecithin powder, agalactomannan, one or more sweetening agents, one or more flavoringagents and an organic acid in a pharmaceutically acceptable preparation.In various embodiments, the dry-powder formulation includes ibuprofen;sunflower lecithin powder; guar gum; xylitol and isomalt; cherry,strawberry and raspberry flavorings and citric acid in apharmaceutically acceptable preparation. In various aspects, theformulation solubility or dispersability in water is no more than about0.5 w/v. In various aspects, the formulation or an aqueous solution ordispersion thereof is in a unit dosage form in a container selected fromthe group consisting of a blister foil pack, stick pack, sachet, pouch,orally disintegrating tablet, dispersible tablet and capsule. In variousaspects, the unit dosage form of ibuprofen is in a quantity of about 50,about 100, about 200, about 400, about 600, or about 800 mg.

Various other embodiments are directed to a method of preparing a drypowder oral formulation of an API. The method includes combining, in anyorder, an API, a lecithin powder, a galactomannan, one or moresweetening agents, one or more flavoring agents and an organic acid in apharmaceutically acceptable preparation. In various embodiments, thedry-powder formulation includes ibuprofen; sunflower lecithin powder;guar gum; xylitol and isomalt; cherry, strawberry and raspberryflavorings and citric acid in a pharmaceutically acceptable preparation.In various aspects, the formulation solubility or dispersability inwater is no more than about 0.5 w/v. In various aspects, the formulationor an aqueous solution or dispersion thereof is in a unit dosage form ina container selected from the group consisting of a blister foil pack,stick pack, sachet, pouch, orally disintegrating tablet, dispersibletablet and capsule. In various aspects, the unit dosage form ofibuprofen is in a quantity of about 50, about 100, about 200, about 400,about 600 or about 800 mg.

In various other embodiments, the present invention is directed to anexcipient composition for combining with an API to produce a drug ornutraceutical composition. The composition includes a lecithin powder, agalactomannan, one or more sweetening agents, one or more flavoringagents and an organic acid in a preparation that when combined with anAPI produces a pharmaceutically acceptable preparation. In variousembodiments, the excipient composition includes a sunflower lecithinpowder; guar gum; xylitol and isomalt; cherry, strawberry and, raspberryflavorings and citric acid.

In various other embodiments, the present invention is directed to a drypowder formulation or an aqueous solution or dispersion thereof asdescribed above comprised within a unit dosage form in a containerselected from the group consisting of a blister foil pack, stick pack,sachet, pouch, bottle, orally disintegrating tablet, dispersible tablet,powder in a capsule, spheres in a capsule, and capsule.

In yet other embodiments, the present invention is directed to achewable, swallowable, and/or orally disintegrating tablet comprising anactive pharmaceutical ingredient (API), a lecithin powder, agalactomannan, one or more sweetening agents, one or more flavoringagents and an organic acid in a pharmaceutically acceptable preparation.

These and other features, aspects and advantages of the presentteachings will become better understood with reference to the followingdescription, examples and appended claims.

DRAWINGS

No drawings are submitted with this application.

DETAILED DESCRIPTION

The present invention is directed to formulations for orallyadministering substances in a dry powder form or with a small quantityof water and to methods for preparing and administering theformulations.

As used herein, the following terms are defined with the followingmeanings, unless explicitly stated otherwise.

The term “about” when used before a numerical designation, e.g., pH,temperature, quantity, concentration, and molecular weight, includingrange, indicates approximations which may vary by ±5%, ±1%, or ±0.1%.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise. For example, the term “a pharmaceutically acceptable carrier”may include a plurality of pharmaceutically acceptable carriers,including mixtures thereof.

The term “and/or” is intended to mean either or both of two componentsof the invention.

The term “subject,” “individual” or “patient” is used interchangeablyherein, and refers to a human.

The term “device,” as used herein, refers to an apparatus or systemcapable of delivering a drug to patient in need thereof.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably and refer to a judgmentmade by a caregiver, e.g. physician, nurse, nurse practitioner, that apatient will benefit from treatment.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent of a pharmaceutical composition that is compatible with theother ingredients of the formulation and not overly deleterious to therecipient thereof.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which the therapeutic is administered and includes, but is notlimited to such liquids and powders that are hydrophilic substances,hydrophobic substances and substances that possess both hydrophilic andhydrophobic properties such as emulsifiers.

The term “therapeutically effective amount,” as used herein, refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, or individual thatis being sought by a researcher, healthcare provider or individual.

The term “w/w” as used herein, is intended to refer to mass fraction,i.e., the mass of a component divided by total mass of the whole. Theterm “% w/w” is intended to refer to the mass fraction multiplied by100. Similarly, the term “w/v” refers to volume concentration, i.e., themass of a component divided by total volume of the whole and the term “%w/v” refers to the volume concentration multiplied by 100.

The term “mouthfeel’ as used herein is intended to refer to the physicalsensations in the mouth produced by a particular food or drug.

The term API (active pharmaceutical ingredient) as used herein, refersto the component in a therapeutic medication or nutraceutical substancethat is biologically active.

The term “unit dose” refers to a single drug delivery entity, e.g., atablet, capsule, dry powder, solution, dispersion etc., that isadministered to an individual. The amount administered may varyaccording to numerous factors, including, e.g., the age of theindividual, the weight of the individual, the genetic makeup of theindividual, and the severity of symptoms exhibited by the individual towhom the drug is administered.

The unit dosage form (powder, granulation, tablet, sphere, or capsule)may be packaged into a blister foil pack, a stick pack, a sachet, apouch, a bottle, or any other self-contained unit. The unit dosage formmay optionally be packaged as a dual package whereby the dry component(powder, granulation, tablet, sphere, capsule) may be combined with asolution component in an integrated package.

The term “excipient” as used herein is intended to mean components of adrug formulation other than the API that are added to a drug formulationto perform a specific function in the finished drug product. Theexcipient may aid in dissolution or dispersion of the API, beneficiallyalter the mouthfeel of the drug product, improve the taste profile ofthe drug product among other things. An excipient composition isintended to refer to a combination of a plurality of excipients that canbe added to an API to produce a finished drug product.

The term NSAID (non-steroidal anti-inflammatory drug) as used herein,refers to drugs distinguished as a class from steroid compounds in whichthe drugs provide analgesic, antipyretic and anti-inflammatory effects.Prominent NSAIDs include aspirin, ibuprofen and naproxen although otherNSAIDs include ketoprofen, sulindac, etodolac, fenoprofen, diclofenac,flurbiprofen, ketorolac, piroxicam, indomethacin, mefenamic, meloxicam,nabumetone, oxaprozin, ketoprofen, meclofenamate, tolmetin andsalsalate.

Ibuprofen is an NSAID that is a non-specific cyclooxygenase inhibitoravailable over the counter and generally viewed as being relativelysafe. (9, 10). Ibuprofen is sparingly soluble in water and differentformulations have shown different absorption rates but equivalentbioavailability (11).

In various embodiments, ibuprofen may be present in certain formulationsherein. In such formulations, the ibuprofen may be present in a quantityof from about 1.5% w/w, about 3.0% w/w, about 4.0% w/w, about 5.0% w/wor about 6.0% w/w up to about 9.0% w/w, about 10.0% w/w, about 11.0%w/w, about 12.0% w/w, about 13.0% w/w, about 14.0% w/w or about 15.0%w/w and, in particular, in an amount of about 1.5% w/w, about 3.0% w/w,about 4.0% w/w, about 5.0% w/w, about 6.0% w/w, about 7% w/w, about 7.5%w/w, about 8% w/w, about 9.0% w/w, about 10.0% w/w, about 11.0% w/w,about 12.0% w/w, about 13.0% w/w, about 14.0% w/w or about 15.0% w/w.

Formulations

In various embodiments, the present invention is directed to anexcipient composition comprising a lecithin powder, a galactomannan, oneor more sweetening agents, one or more flavoring agents and an organicacid in a preparation that when combined with an API produces apharmaceutically acceptable preparation.

The invention utilizes functional excipients to produce a powder suchthat the following are achieved:

-   -   1. Acceptable properties of flow, density, compactibility,        suspendability, and dispersability are achieved for powder,        solution, and suspension dosage forms.    -   2. Acceptable flavor profiles (intensity of flavor) and        sufficient taste masking of one or more active pharmaceutical        ingredients in the dosage forms listed in item 1 without the        need for complex taste masking methods.    -   3. The same powder formulation can be processed utilizing but        not limited to dry blending, roller compaction, wet granulation,        spheronization and filled into foil/stick packs/sachets/pouches,        compressed into chewable/swallowable/quick dissolving tablets        and filled into capsules.    -   4. The invention allows for the powder dosage form to quickly        dissolve in the mouth or the powder can be readily dissolved or        suspended and dispersed using a small quantity of water and then        taken by mouth.

In various embodiments, the formulation is a dispersion comprisingibuprofen, guar, lecithin, and flavors. In such a dispersion, isomalt,xylitol, citric acid, can be solubilized. In various other embodiments,the formulation can comprise components which are all solubilized.

Lecithin refers to a group of amphiphilic, surfactant compoundsnaturally occurring in plant and animal tissue and pharmaceuticallyuseful as emulsifying agents. Lecithins can be found in fish, eggs,milk, soybeans, cotton seed, rapeseed and sunflower seeds. Chemically,the central structure of lecithin is a glycerol group with esterlinkages to two long chain fatty acid groups and to an orthophosphategroup. The orthophosphate group is then linked by an ester bond to astrongly basic choline group (12). The resultant molecule as shown belowis a surfactant:

In processing from plant sources, the extract may be in oily liquid formas a result of the presence of liquid oily components which when furtherremoved yields a granular or powder product.

Sunflower lecithin powder contains phosphatidyl choline, phosphatidylinositol, phosphatidyl ethanolamine, and phosphatidic acid. In contrastto this, lecithin oil additionally contains oily components that resultin the composition being in the form of an oily liquid.

The term “lecithin” or “lecithin powder” as used herein is intended toreference lecithin in powder or granular form and not lecithin oil.

The lecithin powder may be present in the excipient composition as wellas in compositions containing an API and the excipient composition in anamount of from about 0.1% w/w, about 0.2% w/w, about 0.4% w/w up toabout 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w or about1.0% w/w and, in particular, in an amount of about 0.1% w/w, about 0.2%w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w,about 0.7% w/w, about 0.8% w/w, about 0.9% w/w or about 1.0% w/w.

The term “galactomannan” refers to a polysaccharide containing a mannosebackbone and galactose side groups. Galactomannans may have a mannose togalactose ratio of from about 1:1 to about 4:1 and non-limiting examplesinclude fenugreek gum, guar gum, tara gum and locust bean gum. Guar gum,in particular, may be useful as a component in the formulations herein.

The galactomannan, guar gum (mannose:galactose˜2:1) may be present inthe excipient composition as well as in compositions containing an APIand the excipient composition in an amount of from about 0.05% w/w,about 0.1% w/w, about 0.2% w/w up to about 0.3% w/w, about 0.35% w/w,about 0.4% w/w, about 0.45% w/w or about 0.5% w/w and, in particular, inan amount of about 0.05% w/w, about 0.1% w/w, about 0.15% w/w, about0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4%w/w, about 0.45% w/w or about 0.5% w/w.

Sweetening agents such as sugar alcohols, in particular, may be usefulin the formulations herein. Sugar alcohols are polyols that may bederived from sugars in which either the aldehyde or the keto group maybe reduced. These may include (with chain length indicated inparentheses): glycerol (3-carbon), erythritol (4-carbon), threitol(4-carbon), arabitol (5-carbon), xylitol (5-carbon), ribitol (5-carbon),mannitol (6-carbon), sorbitol, (6-carbon), galactitol (6-carbon),fucitol (6-carbon), iditol (6-carbon), inositol (6-carbon cyclic sugaralcohol), volemitol (7-carbon), isomalt (12-carbon), maltitol(12-carbon), lactitol (12-carbon), maltotriitol (18-carbon) andmaltotetraitol (24-carbon). Xylitol and isomalt, in particular, may beuseful in the formulations herein. Xylitol may be present in theexcipient composition as well as in compositions containing an API andthe excipient composition in an amount of from about 1% w/w, about 5%w/w, about 10% w/w or about 15% w/w up to about 25% w/w, about 30% w/w,about 35% w/w or about 40% w/w and, in particular, in an amount of about5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w,about 30% w/w, about 35 o about 40% w/w.

Isomalt may be present in the excipient composition as well as incompositions containing an API and the excipient composition in anamount of from about 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35%w/w, 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/wor about 65% w/w up to about 75% w/w, about 80% w/w or about 85% w/wand, in particular, in an amount of about 40% w/w, about 45% w/w, about50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w,about 75% w/w, about 80% w/w, about 85% w/w, or about 90% w/w. Otherfillers or diluents can include dextrins, maltodextrins, fructose, andthe like in the same amounts. Those of skill in the art will recognizeother fillers and diluents suitable in the present formulation.

Flavoring agents may also be included in the formulations herein.Flavoring agents are additives that modify or enhance the taste and thearoma of orally consumed substances. Examples of the flavoring agentthat may be used in the formulations herein include fruity flavoringagents such as cherry, strawberry and raspberry as well as otherflavoring agents such as peppermint, spearmint, lemon, etc. Cherry,strawberry and raspberry flavorings, in particular, may be useful in theformulations herein.

The cherry, strawberry and raspberry flavoring, may be present in theexcipient composition as well as in compositions containing an API andthe excipient composition in an amount of from about 0.02% w/w, about0.04% w/w, about 0.08% w/w, about 0.1% w/w, about 0.2% w/w, about 0.4%w/w, about 0.8% w/w up to about 1.2% w/w, about 1.4% w/w, about 1.6%w/w, about 1.8% w/w or about 2.0% w/w and, in particular, in an amountof about 0.02% w/w, about 0.04% w/w, about 0.08% w/w, about 0.1% w/w,about 0.2% w/w, about 0.4% w/w, about 0.6% w/w, about 0.8% w/w, about1.0% w/w, about 1.2% w/w, about 1.4% w/w, about 1.6% w/w, about 1.8%w/w, about 2.0% w/w, or about 3% w/w.

The formulations herein may also include an organic acid such as citricacid, tartaric acid, ascorbic acid, fumaric acid, malic acid, adipicacid, succinic acid etc. Citric acid, in particular, may be useful inthe formulations herein.

Citric acid may be present in the excipient composition as well as incompositions containing an API and the excipient composition in anamount of from about 0.025% w/w, about 0.05% w/w, about 0.1% w/w up toabout 0.15% w/w, about 0.175% w/w, about 0.2% w/w, about 0.225 w/w orabout 0.25 w/w and, in particular, in an amount of about 0.025% w/w,about 0.05% w/w, about 0.0755% w/w, about 0.1% w/w, about 0.125% w/w,about 0.15 w/w, about 0.175 w/w, about 0.2% w/w, about 0.225 w/w orabout 0.25% w/w. Other acidulants may be included in the presentformulation in the same amounts, such as malic acid, formic acid, andthe like. Those of skill in the art will recognize other acidulantsuseful in the present formulation.

The formulations herein may be processed by dry blending, rollercompaction, wet granulation, spheronization and filled into foil/stickpacks/sachets/pouches, compressed into chewable/swallowable/quickdissolving tablets and filled into capsules.

EXAMPLES

Aspects of the present teachings may be further understood in light ofthe following examples, which should not be construed as limiting thescope of the present teachings in any way. Unless otherwise indicated,the amount of formulation tested was 1.33 g or 2.66 g, which will beidentified in the context of the examples below.

Example 1

This example evaluated a prototype formula with Isomalt to ascertainpreliminary information on mouth feel, flavor intensity, and sweetness.

TABLE 1a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)500.0 100.0 100 50

TABLE 1B % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI Group 7050-3921 20.000100.000 10.000 0.010 USP Isomalt Beneo L1216907U2 79.800 399.000 39.9000.040 (Galen IQ) GMBH Natural Virginia S79317 0.100 0.500 0.050 0.000Cherry Dare Flavor CX91 #32839 Edicol 60- Lucid 152/2016 0.100 0.5000.050 0.000 70 (guar gum) TOTAL 100.000 500.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen and Isomalt through a #20 screen.    -   2. Screen flavor through a #40 screen.    -   3. Add the following into a plastic bag in the following order:        -   a. ½ Isomalt        -   b. Ibuprofen        -   c. flavor        -   d. Guar gum        -   e. ½ Isomalt    -   4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

There was no bitter taste in mouth with a little to moderate burn in thethroat. Flavor intensity was not enough.

Example 2

This example evaluated a formula with Xylitol to lessen throat burning,increase flavor, and increase sweetness.

TABLE 2a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)500.0 100.0 100 50

TABLE 2B % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI Group 7050-3921 20.000100.000 10.000 0.010 USP Xylitol Dupont 1942791649 78.900 394.500 39.4500.039 (Xivia CM170) Natural Virginia S79317 1.000 5.000 0.500 0.001Cherry Dare Flavor CX91 #32839 Edicol 60- Lucid 152/2016 0.100 0.5000.050 0.000 70 (guar gum) TOTAL 100.000 500.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 screen.    -   3. Add the following into a plastic bag in the following order:        -   a. ½ Xylitol        -   b. Ibuprofen        -   c. flavor        -   d. Guar gum        -   e. ½ Xylitol    -   4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

There was some bitterness in mouth and some burning. Flavor intensityneeds to be improved. Sweetness level seemed acceptable. Body may beimproved by increasing gum level.

Example 3

This example evaluated a formulation with Xylitol to lessen throatburning and with increased flavor and sweetness components.

TABLE 3a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 3B % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 43.875 438.750 21.9380.022 (Galen IQ) GMBH Xylitol Dupont 1942791649 43.875 438.750 21.9380.022 (Xivia CM170) All Natural Virginia S79317 2.000 20.000 1.000 0.001Cherry Dare Flavor CX91 #32839 Edicol 60-70 Lucid 152/2016 0.250 2.5000.125 0.000 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 screen.    -   3. Add the following into a plastic bag in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. flavor        -   d. Guar gum        -   e. Xylitol    -   4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

There was very little burning after formulation was completely wetted inthe mouth. Sweetness was acceptable. Flavor needs to be more intense.Mouthfeel was acceptable.

When taken wet with 5 g of filtered water, flavor and sweetness wascomparable to dry intake with very low level of burning.

This Formula went into solution easily except that the ibuprofen seemedto agglomerate and form a film at the top. The formulation needs anatural surfactant so that the ibuprofen will disperse uniformly intothe water.

Example 4

This example evaluated a formulation with a 3:1 ratio of Isomalt toXylitol and with increased flavor concentration.

TABLE 4a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 4b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.1570.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.437 214.370 10.7190.011 (Xivia CM170) All Natural Virginia S79317 4.000 40.000 2.000 0.002Cherry Dare Flavor CX91 #32839 Edicol 60-70 Lucid 152/2016 0.250 2.5000.125 0.000 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 screen.    -   3. Add the following into a plastic bag in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. flavor        -   d. Guar gum        -   e. Xylitol    -   4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

Sweetness was acceptable, however it might be desirable to add moresweetener. There was no bitter taste and virtually no burning. Flavorintensity was improved. Mouthfeel was acceptable.

Example 5

This example evaluated the replacement of Virginia Dare (VD) Cherry withGold Coast (GC) Organic Cherry at the same concentration.

TABLE 5a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 5b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.1570.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.437 214.370 10.7190.011 (Xivia CM170) Organic Gold 12/2/2016 4.000 40.000 2.000 0.002Cherry Coast Flavor #650818 Edicol 60-70 Lucid 152/2016 0.250 2.5000.125 0.000 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 screen.    -   3. Add the following into a plastic bag in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. flavor        -   d. Guar gum        -   e. Xylitol    -   4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

There was no bitter taste or burning. Cherry flavor is a juicy brightflavor that is very good. Mouthfeel was acceptable and sufficientlysweet.

When taken wet with 5 ml of water, a significant portion of undissolvedpowder filmed and agglomerated on top of the water surface. Sweetnessand flavor intensity was similar to that when taken dry and burning wastoo apparent.

Example 6

This example compares Strawberry and Raspberry Flavors from VD and GC atthe same concentration as Cherry flavoring.

TABLE 6a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 6b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.1570.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.437 214.370 10.7190.011 (Xivia CM170) IBU-006-1 All Natural Virginia S79315 4.000 40.0002.000 0.002 Strawberry Dare Flavor #34775 IBU-006-2 All Natural VirginiaS79313 Raspberry Dare Flavor #26507 IBU-006-3 Organic Gold 12/2/2016Strawberry Coast Flavor #311904 IBU-006-4 Organic Gold 12/2/2016Raspberry Coast Flavor #325361 Edicol 60- Lucid 152/2016 0.250 2.5000.125 0.000 70 (guar gum) TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 screen.    -   3. Add the following into a plastic bag in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. flavor        -   d. Guar gum        -   e. Xylitol    -   4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

IBU-006-1: Taste was pleasant and not bitter and with very littleburning after rinsing mouth with water.

IBU-006-2: Flavor did not taste mask as well as formulation IBU-006-1.Bitterness and burning were apparent. The powder blend had a pink colordue to flavoring.

IBU-006-3: Flavor was very pleasant with no bitterness or burning.

IBU-006-4: Flavor was Intense with no bitterness or burning.

Example 7

This example compared VD Cherry-Strawberry to GC Cherry-Strawberrycombinations at the same ratio and total concentrations.

TABLE 7a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 7b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.1570.032 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 21.437 214.37010.719 0.011 CM170) IBU-007-1 All Natural Virginia S79317 2.000 20.0001.000 0.001 Cherry Flavor Dare CX91 #32839 All Natural Virginia S793152.000 20.000 1.000 0.001 Strawberry Dare Flavor #34775 IBU-007-1 OrganicGold 12/2/2016 2.000 20.000 1.000 0.001 Cherry Flavor Coast #650818Organic Gold 12/2/2016 2.000 20.000 1.000 0.001 Strawberry Coast Flavor#311904 Edicol 60-70 Lucid 152/2016 0.250 2.500 0.125 0.000 (guar gum)TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 screen.    -   3. Add the following into a plastic bag in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. flavor        -   d. Guar gum        -   e. Xylitol    -   4. Blend by rotating the bag at a consistent pace for 3 minutes

Results:

IBU-007-1: With 1 g sample, flavor combination was pleasant with nobitterness and minor burning after completely wetted in the mouth.Strawberry flavor was dominant.

IBU-007-2: With 1 g sample, flavor combination was very good with noburning or bitterness after completely wetted in the mouth. Strawberryflavor was dominant. With larger amount of 2 g, the cherry andstrawberry flavors could be detected with no bitterness or burning aftercomplete wetted in the mouth by swishing the suspension around in themouth.

Example 8

This example compared VD Cherry-Strawberry-Raspberry flavorings to GCCherry-Strawberry-Raspberry flavorings.

TABLE 8a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 8b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.313 643.130 32.1570.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.437 214.370 10.7190.011 (Xivia CM170) IBU-008-1 All Natural Virginia S79317 1.340 13.4000.670 0.001 Cherry Dare Flavor CX91 #32839 All Natural Virginia S793151.330 13.300 0.665 0.001 Strawberry Dare Flavor #34775 All NaturalVirginia S79313 1.330 13.300 0.665 0.001 Raspberry Dare Flavor #26507IBU-008-2 Organic Gold 12/2/2016 1.340 13.400 0.670 0.001 Cherry CoastFlavor #650818 Organic Gold 12/2/2016 1.330 13.300 0.665 0.001Strawberry Coast Flavor #311904 Organic Gold 12/2/2016 1.330 13.3000.665 0.001 Raspberry Coast Flavor #325361 Edicol 60- Lucid 152/20160.250 2.500 0.125 0.000 70 (guar gum) TOTAL 100.000 1000.000 50.0000.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 screen.    -   3. Add the following into a plastic bag in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. flavor        -   d. Guar gum        -   e. Xylitol    -   4. Blend by rotating the bag at a consistent pace for 3 minutes.

Results:

IBU-008-1: With 2 g sample, flavor was very pleasant with good balance,spicy after notes, no bitterness and little burning in throat.

IBU-008-2: With 2 g sample, flavor was very pleasant with strawberrydominance, no bitterness and some irritation in throat.

Example 9

This example evaluated Sunflower Lecithin to aid in dispersion ofIbuprofen in suspension form. Also evaluated were a reduced amount ofstrawberry flavoring.

TABLE 9a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 9a % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.373 643.730 32.1870.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.457 214.570 10.7290.011 (Xivia CM170) IBU-009-1 All Natural Virginia S79317 1.340 13.4000.670 0.001 Cherry Dare Flavor CX91 #32839 All Natural Virginia S793151.000 10.000 0.500 0.001 Strawberry Dare Flavor #34775 All NaturalVirginia S79313 1.330 13.300 0.665 0.001 Raspberry Dare Flavor #26507IBU-009-2 Organic Gold 12/2/2016 1.340 13.400 0.670 0.001 Cherry CoastFlavor #652865 Organic Gold 12/2/2016 1.000 10.000 0.500 0.001Strawberry Coast Flavor #400938 Organic Gold 12/2/2016 1.330 13.3000.665 0.001 Raspberry Coast Flavor #325361 Edicol 60-70 Lucid 152/20160.250 2.500 0.125 0.000 (guar gum) Sunflower Now None on 0.250 2.5000.125 0.000 Lecithin container TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and lecithin through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

IBU-009-2: With 2 g dry sample, there was good flavor balance with verylittle drug bitterness or burning.

With 2 g sample in 1 tsp. water, flavor was good with no drug bitternessor burning. Suspension was white, cloudy and uniform.

With 2 g in 2 tsp. water flavor was lighter with adequate sweetness.Suspension was white cloudy, and uniform.

Example 10

This example evaluated a formulation containing GC Cherry with VDStrawberry and Raspberry.

TABLE 10a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 10b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 64.126 641.260 32.0630.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.374 213.740 10.6870.011 (Xivia CM170) Organic Gold 12/2/2016 1.500 15.000 0.750 0.001Cherry Coast Flavor #652865 All Natural Virginia S79315 1.000 10.0000.500 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S793131.500 15.000 0.750 0.001 Raspberry Dare Flavor #26507 Edicol 60-70 (guarLucid 152/2016 0.250 2.500 0.125 0.000 gum) Sunflower Now None on 0.2502.500 0.125 0.000 Lecithin container TOTAL 100.000 1000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 and lecithin through a #100        screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2 g dry sample, there was excellent balance of flavor with nobitterness and very low irritation and burning.

With 2 g in 1 tsp. water, the suspension was light pink color and cloudywith a few dark specs coming from raspberry. These dissolved with alittle more shaking. Flavor was good with little throat irritation.

With 2 g dry sample swallowed, flavor was excellent with no bitternessand low to moderate throat irritation which went away in a few minutes.

Example 11

This example evaluated a blend with 5% Ibuprofen to reduce or eliminatethroat irritation.

TABLE 11a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)2,000.0 100.0 25 50

TABLE 11b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 5.000 100.0002.500 0.003 USP Isomalt Beneo L1216907U2 67.876 1357.520 33.938 0.034(Galen IQ) GMBH Xylitol Dupont 1942791649 22.624 452.480 11.312 0.011(Xivia CM170) Organic Gold 12/2/2016 1.500 30.000 0.750 0.001 CherryCoast Flavor #652865 All Natural Virginia S79315 1.000 20.000 0.5000.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.50030.000 0.750 0.001 Raspberry Dare Flavor #26507 Edicol 60-70 (guar Lucid152/2016 0.250 5.000 0.125 0.000 gum) Sunflower Now None on 0.250 5.0000.125 0.000 Lecithin container TOTAL 100.000 2000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 and lecithin through a #100        screen. (lecithin was difficult to screen through #100).    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 4 g dry sample taste was excellent with no bitterness and virtuallyno throat irritation. The amount of powder in the mouth was too much.

With 4 g sample in 1 tsp. water, swallowed, the suspension was lightpink and cloudy with excellent dispersion and good flavor, goodmouthfeel, no bitterness and virtually no irritation.

Example 12

This example evaluated a blend with peppermint at 0.25% to reduce oreliminate throat irritation.

TABLE 12a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 12b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 63.938 639.380 31.9690.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.312 213.120 10.6560.011 (Xivia CM170) Organic Gold 12/2/2016 1.500 15.000 0.750 0.001Cherry Coast Flavor #652865 All Natural Virginia S79315 1.000 10.0000.500 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S793131.500 15.000 0.750 0.001 Raspberry Dare Flavor #26507 Organic Gold12/2/2016 0.250 2.500 0.125 0.000 Peppermint Coast Flavor #315160 Edicol60-70 (guar Lucid 152/2016 0.250 2.500 0.125 0.000 gum) Sunflower NowNone on 0.250 2.500 0.125 0.000 Lecithin container TOTAL 100.0001000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 and lecithin through a #40        screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2 g dry sample swallowed, there was not enough peppermint whichcould hardly be detectable and no bitterness, but too much throat burn.

Example 13

This example evaluated a blend with Peppermint at 1% to reduce oreliminate throat irritation.

TABLE 13a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 50 50

TABLE 13b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 10.000100.000 5.000 0.005 USP Isomalt Beneo L1216907U2 63.375 633.750 31.6880.032 (Galen IQ) GMBH Xylitol Dupont 1942791649 21.125 211.250 10.5630.011 (Xivia CM170) Organic Gold 12/2/2016 1.500 15.000 0.750 0.001Cherry Coast Flavor #652865 All Natural Virginia S79315 1.000 10.0000.500 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S793131.500 15.000 0.750 0.001 Raspberry Dare Flavor #26507 Organic Gold12/2/2016 1.000 10.000 0.500 0.001 Peppermint Coast Flavor #315160Edicol 60-70 (guar Lucid 152/2016 0.250 2.500 0.125 0.000 gum) SunflowerNow None on 0.250 2.500 0.125 0.000 Lecithin container TOTAL 100.0001000.000 50.000 0.050

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 and lecithin through a #40        screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2 g dry sample swallowed, the cool mint and fruit flavor of thecombination was excellent with no bitterness and little throatirritation.

Example 14

This example evaluated a blend with 7.5% concentration of Ibuprofen toreduce or eliminate throat irritation.

TABLE 14a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,333.3 100.0 38.0 50.667

TABLE 14b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI group 7050-3921 7.500 100.0003.800 0.004 USP Isomalt Beneo L1216907U2 66.000 880.000 33.440 0.033(Galen IQ) GMBH Xylitol Dupont 1942791649 22.000 293.333 11.147 0.011(Xivia CM170) Organic Gold 12/2/2016 1.500 20.000 0.760 0.001 CherryCoast Flavor #652865 All Natural Virginia S79315 1.000 13.333 0.5070.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.50020.000 0.760 0.001 Raspberry Dare Flavor #26507 Edicol 60-70 (guar Lucid152/2016 0.250 3.333 0.127 0.000 gum) Sunflower Now None on 0.250 3.3330.127 0.000 Lecithin container TOTAL 100.000 1333.333 50.667 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 and lecithin through a #40        screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample, swallowed, flavor was excellent with nobitterness and very little throat burning.

With 2.666 g sample in 1 tsp. water, flavor was excellent with nobitterness and no throat burning.

Example 15

This example evaluated an agglomeration blending approach for Ibuprofenand Lecithin with 50:50 ratio of Ibuprofen to Lecithin.

Ibuprofen/Lecithin Agglomeration/Coating/Granulation formulation.

TABLE 15a Batch Total % Lecithin Total Weight Coating in H₂O % Solids inH₂O (g) (g) H₂O (g) 82.9 11.000 13.269 70.8 2.269

TABLE 15b Lot % in g/batch kg/batch Ingredient Vendor Number Granulationsize size Ibuprofen, SI 7050- 50.000 5.500 0.006 USP group 3921Sunflower Now None on 50.000 5.500 0.006 Lecithin container TOTAL100.000 11.000 0.011

The following process was used.

-   -   1. Screen lecithin through #40 screen.    -   2. Screen Ibuprofen through #20 screen.    -   3. Blend lecithin and ibuprofen for 3 minutes.    -   4. Weigh water in Suitable container. Add incrementally with        stirring until an agglomeration is achieved.    -   5. Dry at room temperature until thoroughly dry.    -   6. Screen granulation through a #20 screen.

Results:

The agglomeration was too elastic too screen into powder.

Example 16

This example evaluated an agglomeration blending approach for ibuprofenand lecithin with 90:10 ratio of ibuprofen to lecithin.

Ibuprofen/Lecithin Agglomeration/Coating/Granulation formulation.

TABLE 16a Batch Total % Lecithin Total Weight Coating in H₂O % Solids inH₂O (g) (g) H₂O (g) 82.7 6.112 7.391 32.3 1.279

TABLE 16b Lot % in g/batch kg/batch Ingredient Vendor Number Granulationsize size Ibuprofen, SI group 7050-3921 90.000 5.501 0.006 USP SunflowerNow None on 10.000 0.611 0.001 Lecithin container TOTAL 100.000 6.1120.006

The following process was used.

-   -   1. Screen lecithin through #40 screen.    -   2. Screen Ibuprofen through #20 screen.    -   3. Blend lecithin and ibuprofen for 3 minutes.    -   4. Weigh water in Suitable container. Add incrementally with        stirring until an agglomeration is achieved.    -   5. Dry at room temperature until thoroughly dry.    -   6. Screen granulation through a #20 screen.

Powder fill formulation

TABLE 16c Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,000.0 100.0 45 45

TABLE 16d % Granulation % in mg in g/batch kg/batch Ingredient VendorLot Number in Blend Blend blend size sizeAgglomeration-Coating-Granulation Ibuprofen, SI 7050-3921 11.111 10.000100.000 4.500 0.005 USP group Sunflower Now None on 1.111 11.111 0.5000.001 Lecithin container TOTAL 111.111 5.000 0.005 Powder Blend IsomaltBeneo L1216907U2 — 63.480 634.800 28.566 0.029 (Galen IQ) GMBH XylitolDupont 1942791649 — 21.159 211.590 9.522 0.010 (Xivia CM170) OrganicGold 12/2/2016 — 1.500 15.000 0.675 0.001 Cherry Coast Flavor #652865All Virginia S79315 — 1.000 10.000 0.450 0.000 Natural Dare StrawberryFlavor #34775 All Virginia S79313 — 1.500 15.000 0.675 0.001 NaturalDare Raspberry Flavor #26507 Edicol 60-70 (guar Lucid 152/2016 — 0.2502.500 0.113 0.000 gum) TOTAL 100.000 1000.001 45.000 0.045

The blend Process was as follows.

-   -   1. Screen Isomalt and Xylitol through a #20 screen.    -   2. Screen flavors through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen-lecithin granulation        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

Blend did not appear uniform. It was screened through a #40 mesh andre-blended for 3 minutes.

With 2 g dry sample, swallowed, there was no bitter, but there wasconsiderable burning on tongue. There was no throat irritation.

Example 17

This example evaluated a blend of 7.5% Ibuprofen with Lecithin at 0.5%.

TABLE 17a Blend Fill Batch Weight (mg) API (mg) Batch (units) Weight (g)1,333.3 100.0 38.0 50.665

TABLE 17b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, SI 7050-3921 7.500 100.000 3.8000.004 USP group Isomalt Beneo L1216907U2 67.550 900.644 34.224 0.034(Galen IQ) GMBH Xylitol Dupont 1942791649 19.800 263.993 10.032 0.010(Xivia CM170) Organic Gold 12/2/2016 1.650 21.999 0.836 0.001 CherryCoast Flavor #652865 All Natural Virginia S79315 1.100 14.666 0.5570.001 Strawberry Dare Flavor #34775 All Natural Virginia S79313 1.65021.999 0.836 0.001 Raspberry Dare Flavor #26507 Edicol 60-70 (guar Lucid152/2016 0.250 3.333 0.127 0.000 gum) Sunflower Now None on 0.500 6.6670.253 0.000 Lecithin container TOTAL 100.000 1333.303 50.665 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 and lecithin through a #40        screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample swallowed, the flavor was intense and sweetnessgood with no bitterness and very little throat irritation which wentaway in about 3 minutes.

With 2.666 g sample in 1 tsp. water, sample dispersed easily to yield apink cloudy dispersion. The flavor was intense with good sweetness withno bitterness and virtually no throat irritation.

Example 18

This example evaluated an agglomeration blending approach for Ibuprofenand Lecithin with 90:10 ratio of Ibuprofen to Lecithin.

Ibuprofen/Lecithin Agglomeration/Coating/Granulation formulation.

TABLE 18a Batch % Weight Total Lecithin Total % Solids in H₂O (g)Coating (g) in H₂O H₂O (g) 100.0 7.000 7.000 100.0 0.000

TABLE 18b Lot % in g/batch kg/batch Ingredient Vendor Number Granulationsize size Ibuprofen, SI 7050- 80.000 5.600 0.006 USP group 3921Sunflower Now None on 20.000 1.400 0.001 Lecithin container TOTAL100.000 7.000 0.007

The following process was used.

-   -   1. Screen lecithin through #40 screen.    -   2. Screen Ibuprofen through #20 screen.    -   3. Blend lecithin and ibuprofen for 3 minutes.    -   4. Weigh water in Suitable container. Add incrementally with        stirring until an agglomeration is achieved.    -   5. Dry at room temperature until thoroughly dry.    -   6. Screen granulation through a #40 screen.

Results.

Agglomeration tastes very bitter. so that blend with additionalcomponents was not made.

Example 19

This example evaluated an agglomeration blending approach for Ibuprofenand Lecithin with 50:50 ratio of Ibuprofen to Lecithin using a lowquantity of water.

Ibuprofen/Lecithin Agglomeration/Coating/Granulation formulation.

TABLE 19a Batch Total % Total % Solids Weight Coating Lecithin in H₂O inH₂O (g) (g) H₂O (g) 100.00 14.000 14.000 100.0 0.000

TABLE 19b Lot % in g/batch kg/batch Ingredient Vendor Number Granulationsize size Ibuprofen, SI 7050- 50.000  7.000 0.007 USP group 3921Sunflower Now None on 50.000  7.000 0.007 Lecithin container TOTAL100.000  14.000 0.014

The following process was used.

-   -   1. Screen lecithin through #40 screen.    -   2. Screen Ibuprofen through #20 screen.    -   3. Blend lecithin and ibuprofen for 3 minutes.    -   4. Weigh water in Suitable container. Add incrementally with        stirring until an agglomeration is achieved (0.471 g H₂O).    -   5. Dry at room temperature until thoroughly dry.    -   6. Screen granulation.

Results:

400 mg agglomeration was swallowed dry with some bitterness and a littlethroat irritation detected.

Granules were too soft and no further blending was done.

Example 20

This example evaluated 7.5% formulation with Citric Acid at 0.5%, 0.25%and 0.125%.

TABLE 20a Bulk Blend. (IBU-20) Blend Fill Batch Batch Weight (mg) API(mg) (units) Weight (g) 1,333.3 100.0 38.0 50.665

TABLE 20b Bulk Blend. (IBU-20). % mg/blend g/batch kg/batch IngredientVendor Lot Number Concentration fill size size Ibuprofen, SI group7050-3921 7.500 100.000 3.800 0.004 USP Isomalt Beneo L1216907U2 67.550900.644 34.224 0.034 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800263.993 10.032 0.010 (Xivia CM170) Organic Gold 12/2/2016 1.650 21.9990.836 0.001 Cherry Coast Flavor #652865 All Natural Virginia S793151.100 14.666 0.557 0.001 Strawberry Dare Flavor #34775 All NaturalVirginia S79313 1.650 21.999 0.836 0.001 Raspberry Dare Flavor #26507Edicol 60-70 (guar Lucid 152/2016 0.250 3.333 0.127 0.000 gum) Lipoid HLipoid 536900- 0.500 6.667 0.253 0.000 20 GMBH 2160013 SunflowerLecithin TOTAL 100.000 1333.303 50.665 0.051

The following process was used.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor through a #40 and lecithin through a #40        screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. flavor        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

TABLE 20c Citric Acid 0.5% (IBU-20-1). Blend Fill Batch Batch Weight(mg) API (mg) (units) Weight (g) 1,333.3 100.0 7.5 10.000

TABLE 20d Citric Acid 0.5% (IBU-20-1). % mg/blend g/batch kg/batchIngredient Vendor Lot Number Concentration fill size size Ibuprofen, SIgroup 7050-3921 7.500 100.000 0.750 0.001 USP Isomalt Beneo L1216907U267.050 893.978 6.705 0.007 (Galen IQ) GMBH Xylitol Dupont 194279164919.800 263.993 1.980 0.002 (Xivia CM170) Organic Gold 12/2/2016 1.65021.999 0.165 0.000 Cherry Coast Flavor #652865 All Virginia S79315 1.10014.666 0.110 0.000 Natural Dare Strawberry Flavor #34775 All VirginiaS79313 1.650 21.999 0.165 0.000 Natural Dare Raspberry Flavor #26507Edicol 60-70 (guar Lucid 152/2016 0.250 3.333 0.025 0.000 gum) Lipoid HLipoid 536900- 0.500 6.667 0.050 0.000 20 GMBH 2160013 SunflowerLecithin Citric Acid Anthony's 5/16/2019 0.500 6.667 0.050 0.000 AlmondsTOTAL 100.000 1333.303 10.000 0.010

TABLE 20e Citric Acid at 0.25% (IBU-20-2). Blend Fill Batch Batch Weight(mg) API (mg) (units) Weight (g) 1,333.3 100.0 7.5 10.000

TABLE 20f Citric Acid at 0.25% (IBU-20-2) % mg/blend g/batch kg/batchIngredient Vendor Lot Number Concentration fill size size Ibuprofen, USPSI group 7050-3921 7.500  100.000 0.750 0.001 Isomalt Beneo L1216907U267.300   897.311 6.730 0.007 (Galen IQ) GMBH Xylitol (Xivia Dupont1942791649 19.800   263.993 1.980 0.002 CM170) Organic Cherry Gold12/2/2016 1.650  21.999 0.165 0.000 Flavor #652865 Coast All NaturalVirginia S79315 1.100  14.666 0.110 0.000 Strawberry Dare Flavor #34775All Natural Virginia S79313 1.650  21.999 0.165 0.000 Raspberry DareFlavor #26507 Edicol 60-70 Lucid 152/2016 0.250   3.333 0.025 0.000(guar gum) Lipoid H 20 Lipoid 536900- 0.500   6.667 0.050 0.000Sunflower GMBH 2160013 Lecithin Citric Acid Anthony's 5/16/2019 0.250  3.333 0.025 0.000 Almonds TOTAL 100.000  1333.303 10.000  0.010

TABLE 20g Citric Acid at 0.125% (IBU-20-3). Blend Fill Batch BatchWeight (mg) API (mg) (units) Weight (g) 1,333.3 100.0 7.5 10.000

TABLE 20h Citric Acid at 0.125%(IBU-20-3). % mg/blend g/batch kg/batchIngredient Vendor Lot Number Concentration fill size size Ibuprofen, USPSI group 7050-3921 7.500  100.000 0.750 0.001 Isomalt Beneo L1216907U267.425   898.978 6.742 0.007 (Galen IQ) GMBH Xylitol (Xivia Dupont1942791649 19.800   263.993 1.980 0.002 CM170) Organic Cherry Gold12/2/2016 1.650  21.999 0.165 0.000 Flavor #652865 Coast All NaturalVirginia S79315 1.100  14.666 0.110 0.000 Strawberry Dare Flavor #34775All Natural Virginia S79313 1.650  21.999 0.165 0.000 Raspberry DareFlavor #26507 Edicol 60-70 Lucid 152/2016 0.250   3.333 0.025 0.000(guar gum) Lipoid H 20 Lipoid 536900- 0.500   6.667 0.050 0.000Sunflower GMBH 2160013 Lecithin Citric Acid Anthony's 5/16/2019 0.125  1.667 0.012 0.000 Almonds TOTAL 100.000  1333.303 10.000 0.010

The blending process was as follows.

-   -   1. Weigh a 10 g portion of the bulk blend.    -   2. Screen Citric Acid through a #40 screen.    -   3. Blend citric acid with the bulk blend for 1 minute.

TABLE 20i Citric Acid at 0.125% and increased flavorings (IBU-20-4).Blend Fill Batch Batch Weight (mg) API (mg) (units) Weight (g) 1,356.2100.0 7.5 10.172

TABLE 20j Citric Acid at 0.125% and increased flavorings (IBU-20-4). %mg/blend g/batch kg/batch Ingredient Vendor Lot Number Concentrationfill size size Ibuprofen, USP SI group 7050-3921 7.374  100.000  0.7500.001 Isomalt Beneo L1216907U2 65.951   894.427  6.708 0.007 (Galen IQ)GMBH Xylitol (Xivia CM170) Dupont 1942791649 19.800   268.528  2.0140.002 Organic Cherry Gold 12/2/2016 2.000  27.124  0.203 0.000 Flavor#652865 Coast All Natural Virginia S79315 2.000  27.124  0.203 0.000Strawberry Dare Flavor #34775 All Natural Virginia S79313 2.000  27.124 0.203 0.000 Raspberry Dare Flavor #26507 Edicol 60-70 Lucid 152/20160.250   3.391  0.025 0.000 (guar gum) Lipoid H 20 Lipoid 536900- 0.500  6.781  0.051 0.000 Sunflower GMBH 2160013 Lecithin Citric AcidAnthony's 5/16/2019 0.125   1.695  0.013 0.000 Almonds TOTAL 100.000 1356.194 10.171 0.010

The Blend process was as follows.

-   -   1. Weigh a 10 g portion of the bulk blend.    -   2. Screen flavors through a #40 and add the difference.        -   Cherry: 0.035        -   Strawberry: 0.09        -   Raspberry: 0.035    -   3. Screen Citric Acid through a #40 screen.    -   4. Blend Flavors and Citric Acid for 1 minute.    -   TOTAL Weight=10.172 g

Results:

Citric Acid from 0.5-0.25% was too sour.

Citric Acid at 0.125% (IBU-020-3) lessens the sour flavor but does bringout the fruit complex.

IBU-20-4:

With 2.712 g dry sample, flavor was very intense with a little spicenote. Sample was not sour, but brought out a little bit of tartness.Although not swallowed; there was a little bit of throat irritation.

With 2.712 g sample in 1 tsp water, swallowed, flavor and sweetness wereexcellent with no bitterness or throat irritation.

Example 21

This example repeats the IBU-020-4 formulation in Example 29 at a 50 gbatch weight.

TABLE 21a Citric Acid at 0.125% Blend Fill Batch Batch Weight (mg) API(mg) (units) Weight (g) 1,333.3 100.0 38.0 50.665

TABLE 21b Citric Acid at 0.125%, % mg/blend g/batch kg/batch IngredientVendor Lot Number Concentration fill size size Ibuprofen, USP SI group7050-3921 7.500  100.000  3.800 0.004 Isomalt Beneo L1216907U2 65.825  877.645 33.350 0.033 (Galen IQ) GMBH Xylitol Dupont 1942791649 19.800  263.993 10.032 0.010 (Xivia CM170) Organic Cherry Gold 12/2/2016 2.000 26.666  1.013 0.001 Flavor #652865 Coast All Natural Virginia S793152.000  26.666  1.013 0.001 Strawberry Dare Flavor #34775 All NaturalVirginia S79313 2.000  26.666  1.013 0.001 Raspberry Dare Flavor #26507Edicol 60-70 Lucid 152/2016 0.250   3.333  0.127 0.000 (guar gum) LipoidH 20 Lipoid 536900- 0.500   6.667  0.253 0.000 Sunflower GMBH 2160013Lecithin Citric Acid Anthony's 5/16/2019 0.125   1.667  0.063 0.000Almonds TOTAL 100.000  1333.303 50.665 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and citric acid through a #40 and lecithin        through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. Flavors        -   e. Citric acid        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample, swallow flavor and sweetness were excellentwith no bitterness and very little throat irritation.

With 2.666 g sample in 1 tsp. water, swallowed, flavor and sweetnesswere excellent with no bitterness and no throat irritation.

Example 22

This example evaluated the formula in example 21, but with a 25%reduction in flavor components.

TABLE 22a Blend Fill Batch Batch Weight (mg) API (mg) (units) Weight (g)1,333.3 100.0 38.0 50.665

TABLE 22b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, USP SI group 7050-3921 7.500 100.000  3.800 0.004 Isomalt Beneo L1216907U2 67.325   897.644 34.1100.034 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 19.800   263.99310.032 0.010 CM170) Organic Cherry Gold 12/2/2016 1.500  20.000  0.7600.001 Flavor #652865 Coast All Natural Virginia S79315 1.500  20.000 0.760 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S793131.500  20.000  0.760 0.001 Raspberry Dare Flavor #26507 Edicol 60-70Lucid 152/2016 0.250   3.333  0.127 0.000 (guar gum) Lipoid H 20 Lipoid536900- 0.500   6.667  0.253 0.000 Sunflower GMBH 2160013 LecithinCitric Acid Anthony's 5/16/2019 0.125   1.667  0.063 0.000 Almonds TOTAL100.000  1333.303 50.665 0.051

The blend Process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and citric acid through a #40 and lecithin        through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. Flavors        -   e. Citric acid        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample, swallowed, flavor intensity and sweetness weregood with light spicy flavor, no bitterness and little throatirritation.

With 2.666 g sample 1 tsp. water, flavor intensity and sweetness weregood with no bitterness and no throat irritation.

Example 23

This example evaluated a formulation with reduced flavor components (33%reduction compared to example 22).

TABLE 23a Blend Fill Batch Batch Weight (mg) API (mg) (units) Weight (g)1,333.3 100.0 38.0 50.665

TABLE 23b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, USP SI group 7050-3921 7.500 100.000  3.800 0.004 Isomalt Beneo L1216907U2 68.825   917.644 34.8700.035 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 19.800   263.99310.032 0.010 CM170) Organic Cherry Gold 12/2/2016 1.000  13.333  0.5070.001 Flavor #652865 Coast All Natural Virginia S79315 1.000  13.333 0.507 0.001 Strawberry Dare Flavor #34775 All Natural Virginia S793131.000  13.333  0.507 0.001 Raspberry Dare Flavor #26507 Edicol 60-70Lucid 152/2016 0.250   3.333  0.127 0.000 (guar gum) Lipoid H 20 Lipoid536900- 0.500   6.667  0.253 0.000 Sunflower GMBH 2160013 LecithinCitric Acid Anthony's 5/16/2019 0.125   1.667  0.063 0.000 Almonds TOTAL100.000 1333.303 50.665 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and citric acid through a #40 and lecithin        through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. Flavors        -   e. Citric acid        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample, swallowed, flavor intensity and sweetness weregood with no bitterness and little throat irritation

With 2.666 g sample in 1 tsp. water, flavor intensity and sweetness weregood with no bitterness and no throat irritation.

Example 24

This example evaluated a formulation with a change in Cherry flavoringsupplier from GC to VC.

TABLE 24a Blend Fill Batch Batch Weight (mg) API (mg) (units) Weight (g)1,333.3 100.0 38.0 50.665

TABLE 25b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, USP SI group 7050-3921 7.500 100.000  3.800 0.004 Isomalt Beneo L1216907U2 68.825   917.644 34.8700.035 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 19.800   263.99310.032 0.010 CM170) All Natural Virginia S79579 1.000  13.333  0.5070.001 Cherry Flavor Dare #34327 All Natural Virginia S79315 1.000 13.333  0.507 0.001 Strawberry Dare Flavor #34775 All Natural VirginiaS79313 1.000  13.333  0.507 0.001 Raspberry Dare Flavor #26507 Edicol60-70 Lucid 152/2016 0.250   3.333  0.127 0.000 (guar gum) Lipoid H 20Lipoid 536900- 0.500   6.667  0.253 0.000 Sunflower GMBH 2160013Lecithin Citric Acid Anthony's 5/16/2019 0.125   1.667  0.063 0.000Almonds TOTAL 100.000  1333.303 50.665 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and citric acid through a #40 and lecithin        through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. Flavors        -   e. Citric acid        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample swallowed, flavor and sweetness were excellentwith no bitterness and very little throat irritation.

With 2.666 g sample in 1 tsp. water, flavor and sweetness were excellentwith no bitterness and no throat irritation. Overall the VD Cherryflavor is equal or superior to the GC cherry.

Example 25

This example evaluated a change from VD raspberry (color) to VDraspberry (colorless). Otherwise all conditions were the same as inexample 24.

TABLE 25a Blend Fill Batch Batch Weight (mg) API (mg) (units) Weight (g)1,333.3 100.0 38.0 50.665

TABLE 25b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, USP SI group 7050-3921 7.500 100.000  3.800 0.004 Isomalt Beneo L1216907U2 68.825   917.644 34.8700.035 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 19.800   263.99310.032 0.010 CM170) All Natural Virginia S79579 1.000  13.333  0.5070.001 Cherry Flavor Dare #34327 All Natural Virginia S79315 1.000 13.333  0.507 0.001 Strawberry Dare Flavor #34775 All Natural VirginiaS79313 1.000  13.333  0.507 0.001 Raspberry Dare Flavor #20625 Edicol60-70 Lucid 152/2016 0.250   3.333  0.127 0.000 (guar gum) Lipoid H 20Lipoid 536900- 0.500   6.667  0.253 0.000 Sunflower GMBH 2160013Lecithin Citric Acid Anthony's 5/16/2019 0.125   1.667  0.063 0.000Almonds TOTAL 100.000  1333.303 50.665 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and citric acid through a #40 and lecithin        through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. Flavors        -   e. Citric acid        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample, the raspberry flavor was too strong with avolatile essence.

Example 26

This example evaluated a formulation with VD Raspberry (colorless) in anamount (0.5%).

TABLE 26a Blend Fill Batch Batch Weight (mg) API (mg) (units) Weight (g)1,333.3 100.0 38.0 50.665

TABLE 26b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, USP SI group 7050-3921 7.500 100.000  3.800 0.004 Isomalt Beneo L1216907U2 69.325   924.310 35.1240.035 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 19.800   263.99310.032 0.010 CM170) All Natural Virginia S79579 1.000  13.333  0.5070.001 Cherry Flavor Dare #34327 All Natural Virginia S79315 1.000 13.333  0.507 0.001 Strawberry Dare Flavor #34775 All Natural VirginiaS79577 0.500   6.667  0.253 0.000 Raspberry Dare Flavor #20625 Edicol60-70 Lucid 152/2016 0.250   3.333  0.127 0.000 (guar gum) Lipoid H 20Lipoid 536900- 0.500   6.667  0.253 0.000 Sunflower GMBH 2160013Lecithin Citric Acid Anthony's 5/16/2019 0.125   1.667  0.063 0.000Almonds TOTAL 100.000  1333.303 50.665 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and citric acid through a #40 and lecithin        through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. Flavors        -   e. Citric acid        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample, swallowed, flavor was much improved with theraspberry much less overwhelming over the other flavors compared toexample 25 and with a little bit of volatile essence through the nose.

Example 27

This example evaluated a formulation with VD Raspberry (colorless) in anamount (0.25%).

TABLE 27a Blend Fill Batch Batch Weight (mg) API (mg) (units) Weight (g)1,333.3 100.0 38.0 50.665

TABLE 27b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, USP SI group 7050-3921 7.500 100.000  3.800 0.004 Isomalt Beneo L1216907U2 69.575   927.643 35.2500.035 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 19.800   263.99310.032 0.010 CM170) All Natural Virginia S79579 1.000  13.333  0.5070.001 Cherry Flavor Dare #34327 All Natural Virginia S79315 1.000 13.333  0.507 0.001 Strawberry Dare Flavor #34775 All Natural VirginiaS79577 0.250   3.333  0.127 0.000 Raspberry Dare Flavor #20625 Edicol60-70 Lucid 152/2016 0.250   3.333  0.127 0.000 (guar gum) Lipoid H 20Lipoid 536900- 0.500   6.667  0.253 0.000 Sunflower GMBH 2160013Lecithin Citric Acid Anthony's 5/16/2019 0.125   1.667  0.063 0.000Almonds TOTAL 100.000  1333.303 50.665 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and citric acid through a #40 and lecithin        through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. Flavors        -   e. Citric acid        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample, swallowed, raspberry flavor was a little toointense with spice note and no volatile essence or bitterness and littlethroat irritation.

Example 28

This example evaluated a formulation with VD Raspberry (colorless) in anamount of 0.1%.

TABLE 28a Blend Fill Batch Batch Weight (mg) API (mg) (units) Weight (g)1,333.3 100.0 38.0 50.665

TABLE 28b % mg/blend g/batch kg/batch Ingredient Vendor Lot NumberConcentration fill size size Ibuprofen, USP SI group 7050-3921 7.500 100.000  3.800 0.004 Isomalt Beneo L1216907U2 69.725   929.643 35.3260.035 (Galen IQ) GMBH Xylitol (Xivia Dupont 1942791649 19.800   263.99310.032 0.010 CM170) All Natural Virginia S79579 1.000  13.333  0.5070.001 Cherry Flavor Dare #34327 All Natural Virginia S79315 1.000 13.333  0.507 0.001 Strawberry Dare Flavor #34775 All Natural VirginiaS79577 0.100   1.333  0.051 0.000 Raspberry Dare Flavor #20625 Edicol60-70 Lucid 152/2016 0.250   3.333  0.127 0.000 (guar gum) Lipoid H 20Lipoid 536900- 0.500   6.667  0.253 0.000 Sunflower GMBH 2160013Lecithin Citric Acid Anthony's 5/16/2019 0.125   1.667  0.063 0.000Almonds TOTAL 100.000  1333.303 50.665 0.051

The blend process was as follows.

-   -   1. Screen Ibuprofen, Isomalt, and Xylitol through a #20 screen.    -   2. Screen flavor and citric acid through a #40 and lecithin        through a #40 screen.    -   3. Add the following into a plastic cup in the following order:        -   a. Isomalt        -   b. Ibuprofen        -   c. Lecithin        -   d. Flavors        -   e. Citric acid        -   e. Guar gum        -   f. Xylitol    -   4. Blend by rotating the plastic cup at a consistent pace for 3        minutes.

Results:

With 2.666 g dry sample swallowed, flavor intensity was at the rightlevel, but Raspberry was still dominating other flavors with nobitterness and little throat irritation

With 2.666 g sample in 1 tsp. water and no swallowing, flavor intensitywas good.

Example 29

This example evaluated an ibuprofen powder blend compacted into atablet. This is from the same formula as example 28 with the addition of1% Magnesium Stearate added as a lubricant. The target weight of 1.333 gof powder contains a target dose of 100 mg of ibuprofen. Tablets werecompressed on a rotary tablet press.

TABLE 29a Avg. Applied Tablet Weight (g) Statistics Force (kN) No. 1 No.2 No. 3 No. 4 No.5 No. 6 Avg. % RSD 3.68 1.336 1.340 1.338 1.33  1.3251.327 1.333 0.4 4.64 1.325 1.321 1.33  1.322 1.338 1.337 1.329 0.5 5.501.322 1.329 1.331 1.333 1.338 1.328 1.330 0.4 7.00 1.335 1.329 1.3381.332 1.331 1.325 1.332 0.3 8.16 1.338 1.341 1.336 1.337 1.342 1.3441.340 0.2 9.24 1.344 1.358 1.355 1.346 1.348 1.344 1.349 0.4 11.18 1.3641.360 1.364 1.350 1.348 1.370 1.359 0.6

TABLE 29b Avg. Applied Tablet Thickness (mm) Statistics Force (kN) No. 1No. 2 No. 3 No. 4 No.5 No. 6 Avg. % RSD 3.68 5.72 5.68 5.67 5.65 5.625.59 5.66 0.7 4.64 5.48 5.47 5.48 5.49 5.48 5.47 5.48 0.1 5.50 5.34 5.445.40 5.35 5.35 5.36 5.37 0.7 7.00 5.23 5.15 5.16 5.17 5.23 5.23 5.20 0.78.16 5.12 5.07 5.08 5.08 5.09 5.08 5.09 0.3 9.24 4.98 5.02 4.98 4.964.94 4.91 4.97 0.7 11.18 4.86 4.84 4.85 4.87 4.86 4.90 4.86 0.4

TABLE 29c Avg. Applied Diametrical Breaking Force (N) Statistics Force(kN) No. 1 No. 2 No. 3 No. 4 No. 5 No. 6 Avg. % RSD 3.68 11 16 14 14 1516 14 11.9  4.64 18 16 19 17 18 17 18 5.5 5.50 19 22 24 21 20 25 22 9.77.00 30 31 31 27 30 30 30 4.5 8.16 35 39 38 36 34 38 37 4.9 9.24 44 3444 43 43 45 42 8.8 11.18 51 51 52 48 48 51 50 3.1

TABLE 29d Avg. Applied Diametrical Breaking Force (kp) Statistics Force(kN) No. 1 No. 2 No. 3 No. 4 No. 5 No. 6 Avg. %RSD 3.68 1.1 1.6 1.4 1.41.5 1.6 1.5 11.9 4.64 1.8 1.6 1.9 1.7 1.8 1.7 1.8 5.5 5.50 1.9 2.2 2.42.1 2.0 2.5 2.2 9.7 7.00 3.1 3.2 3.2 2.8 3.1 3.1 3.0 4.5 8.16 3.6 4.03.9 3.7 3.5 3.9 3.7 4.9 9.24 4.5 3.5 4.5 4.4 4.4 4.6 4.3 8.8 11.18 5.25.2 5.3 4.9 4.9 5.2 5.1 3.1

The Ibuprofen powder blend was compacted using the following tablettooling: 18 mm round, flat-face tooling according to Table 29A. Theresultant thicknesses of the compacted tablets are provided in Table29B, and the diametrical breaking forces of the resultant tablets areprovided in Tables 29C and 29D.

The data demonstrates that chewable, swallowable and/or orallydisintegrating tablets can be produced with good weight control,acceptable thickness and breaking force.

This formula with the magnesium stearate is functional for the drypowder dosage form, suspension dosage form and the chewable tablet.Those of skill in the art will recognize the other lubricants includingbut not limited to stearic acid, calcium stearate, sodium stearate,sodium stearyl fumarate (PRUV®), talc, and hydrogenated soybean oil(STEROTEX®) can be used in the formula.

Other Embodiments

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the present invention. However, theinvention described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed because these embodiments areintended as illustration of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description which do not depart from thespirit or scope of the present inventive discovery. Such modificationsare also intended to fall within the scope of the appended claims.

REFERENCES CITED

All publications, patents, patent applications and other referencescited in this application are incorporated herein by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent, patent application or other reference wasspecifically and individually indicated to be incorporated by referencein its entirety for all purposes. Citation of a reference herein shallnot be construed as an admission that such is prior art to the presentinvention.

Publications incorporated herein by reference in their entirety include:

-   1. Sabaté E. Adherence to Long Term Therapies: Evidence for Action.    World Health Organization. 2003. Available at:    http://apps.who.int/medicinedocs/pdf/s4883e/s4883e.pdf.-   2. Fass R., et al., Pharmacokinetic comparison of    orally-disintegrating metoclopramide with conventional    metoclopramide tablet formulation in healthy volunteers, (2009)    Aliment Pharmacol Ther 30, 301-306.-   3. Mennella, J A et al., The Bad Taste of Medicines: Overview of    Basic Research on Bitter Taste, Clin Ther (2013) 35:1225-1246.-   4. Walsh, J et al., Playing hide and seek with poorly tasting    paediatric medicines: Do not forget the excipients, Advanced Drug    Delivery Reviews (2014) 73: 14-33.-   5. Kanabar, D. J., A clinical and safety review of paracetamol and    ibuprofen in children, Inflammopharmacol (2017) 25:1-9; 6.-   6. Kelley, B. P., Ibuprofen does not increase bleeding risk in    plastic surgery: a systematic review and meta-analysis, Plast    Reconstr Surg, (2016) 137:1309-1316.-   7. Khalifa, N., et al., Use of ibuprofen sustained release for    treating osteoarthritic pain: findings from 15 general medical    practices in Egypt, Rheumatology: Research and Reviews (2014)    6:49-56.-   8. de Klerk E., Patient compliance in rheumatoid arthritis,    polymyalgia rheumatica, and gout, J Rheumatol, (2003) 30:44-54.-   9. Rainsford K D, Ibuprofen: pharmacology, efficacy and safety,    Inflammopharmacology. (2009) 7:275-342.-   10. Rockwell W B and Ehrlich H P. Ibuprofen in acute-care therapy,    Ann Surg. (1990) 211:78-83.-   11. Shin et al., Pharmacokinetic and pharmacodynamic evaluation    according to absorption differences in three formulations of    ibuprofen, Drug Des Devel Ther. (2017) 11: 135-141.-   12. Elworthy P H, et al., The Physical Chemistry of Lecithins, J    Pharmacy Pharmacol (1956) 8: 1001-1018.

What is claimed is:
 1. A free flowing dry powder oral formulationsuitable for administration in each of an aqueous solution, aqueousdispersion, tablet, and powder dosage form, wherein the formulationcomprises an active pharmaceutical ingredient (API) in an amount fromabout 3% w/w to about 15% w/w, a surfactant or emulsifier in an amountfrom 0.1% w/w to 1% w/w, a galactomannan in an amount from about 0.05%w/w to about 0.5% w/w, isomalt in an amount of from about 60% w/w toabout 90% w/w, one or more flavoring agents in an amount from about 0.5%w/w to about 5% w/w and an organic acid in an amount from about 0.05%w/w to about 0.5% w/w, in a pharmaceutically acceptable preparation. 2.The formulation of claim 1, wherein the API is ibuprofen in an amount ofabout 7.5% w/w.
 3. The formulation of claim 2, wherein the surfactant oremulsifier is present in an amount of about 0.5% w/w.
 4. The formulationof claim 3, wherein the galactomannan is present in an amount of about0.25% w/w.
 5. The formulation of claim 4, wherein the organic acidcomprises citric acid in an amount of about 0.125% w/w.
 6. Theformulation of claim 5, wherein the one or more flavoring agents arepresent in an amount of about 3% w/w.
 7. A formulation suitable for oraladministration in a unit dosage form selected from powder, granulation,tablet, sphere, or capsule, wherein the formulation comprises an activepharmaceutical ingredient (API) in an amount from about 3% w/w to about15% w/w, a surfactant or emulsifier in an amount from 0.1% w/w to 1%w/w, a galactomannan in an amount from about 0.05% w/w to about 0.5%w/w, one or more sweetening agents in an amount of from about 1.0% w/wto about 90% w/w, one or more flavoring agents in an amount from about0.5% w/w to about 5% w/w and an organic acid in an amount from about0.05% w/w to about 0.5% w/w, in a pharmaceutically acceptablepreparation.
 8. The formulation of claim 7, wherein the unit dose formis a tablet.
 9. The formulation of claim 8, wherein the tablet is achewable tablet, a swallowable tablet, or a quick dissolving tablet. 10.The formulation of claim 7, wherein the API is a non-steroidalanti-inflammatory drug (NSAID).
 11. The formulation of claim 10, whereinthe NSAID is ibuprofen.
 12. The formulation of claim 11, wherein thewherein the unit dosage form comprises ibuprofen in an amount of about50, about 75, about 100, about 200, about 400, about 600, or about 800mg.
 13. The formulation of claim 7, wherein the one or more sweeteningagents comprises isomalt.
 14. The formulation of claim 7, wherein theformulation comprises an active pharmaceutical ingredient (API) in anamount of about 7.5% w/w, a surfactant or emulsifier in an amount ofabout 0.5% w/w, a galactomannan in an amount of about 0.25% w/w, isomaltin an amount of from about 60% w/w to about 90% w/w, one or moreflavoring agents in an amount of about 3.0% w/w, and citric acid in anamount of about 0.125% w/w.
 15. The formulation of claim 7, wherein theAPI is selected from the group consisting of aspirin, ibuprofen,naproxen, ketoprofen, sulindac, etodolac, fenoprofen, diclofenac,flurbiprofen, ketorolac, piroxicam, indomethacin, mefenamic, meloxicam,nabumetone, oxaprozin, ketoprofen, meclofenamate, tolmetin andsalsalate.
 16. A method of preparing a dry powder oral formulation of anAPI suitable for administration in each of an aqueous solution, aqueousdispersion, tablet, and powder dosage form, the method comprising,combining, in any order, a) an API in an amount from about 3% w/w toabout 15% w/w, b) a surfactant or emulsifier in an amount from 0.1% w/wto 1% w/w c) a galactomannan in an amount from about 0.05% w/w to about0.5% w/w, d) one or more sweetening agents in an amount from about 1.0%w/w to about 90% w/w, e) one or more flavoring agents in an amount fromabout 0.5% w/w to about 5% w/w, and f) an organic acid in an amount fromabout 0.05% w/w to about 0.5% w/w.
 17. The method of claim 16, whereinthe API is selected from the group consisting of aspirin, ibuprofen,naproxen, ketoprofen, sulindac, etodolac, fenoprofen, diclofenac,flurbiprofen, ketorolac, piroxicam, indomethacin, mefenamic, meloxicam,nabumetone, oxaprozin, ketoprofen, meclofenamate, tolmetin andsalsalate.
 18. The method of claim 16, wherein the API is ibuprofen. 19.The method of claim 16, wherein the sweetening agent comprises isomalt.20. The method of claim 19, wherein the isomalt is present in an amountof from about 60% w/w to about 90% w/w.